Remarkable control of radical cyclization processes of cyclic enyne: total syntheses of (+/-)-methyl gummiferolate, (+/-)-methyl 7beta-hydroxykaurenoate, and (+/-)-methyl 7-oxokaurenoate and formal synthesis of (+/-)-gibberellin a(12) from a common synthetic precursor.

Total syntheses of (+/-)-methyl gummiferolate (13b), (+/-)-methyl 7beta-hydroxykaurenoate (14b), and (+/-)-methyl 7-oxokaurenoate (14d) and a formal synthesis of (+/-)-gibberellin A(12) (15) have been accomplished through the common synthetic precursor, (3aR,7aR)-3,3-dimethyl-7a-(2-propynyl)-3a,4,7,7a-tetrahydroisobenzofuranone (16). The homoallyl-homoallyl radical rearrangement reaction of the monocyclic enyne 25, derived from 16 in two steps, afforded the bicyclo[2.2.2]octane compound 26, which was converted to (+/-)-methyl gummiferolate (13b). In contrast, the radical cyclization of the bicyclic enyne 16 gave the tricyclic lactone 19, leading to (+/-)-methyl 7beta-hydroxykaurenoate (14b) and (+/-)-methyl 7-oxokaurenoate (14d). Transformation of 14d into lactone 20 was carried out in a single step under bromination conditions. This constitutes a formal total synthesis of gibberellin A(12) (15).     

Dimerization of butenolide structures. A biomimetic approach to the dimeric sesquiterpene lactones (+/-)-biatractylolide and (+/-)-biepiasterolide

The biomimetic synthesis of the bisesquiterpene lactones (+/-)-biatractylolide 1 and (+/-)-biepiasterolide 2 via dimerization of the captodative stabilized radical 8 is reported. Atractylon 7 has also been shown to be a possible intermediate during the biosynthesis of biatractylolide 1, biepiasterolide 2, atractylolide 3, and hydroxyatractylolide 4.     

Homolysis of weak Ti-O bonds: experimental and theoretical studies of titanium oxygen bonds derived from stable nitroxyl radicals

Titanium-oxygen bonds derived from stable nitroxyl radicals are remarkably weak and can be homolyzed at 60 degrees C. The strength of these bonds depends sensitively on the ancillary ligation at titanium. Direct measurements of the rate of Ti-O bond homolysis in Ti-TEMPO complexes Cp2TiCl(TEMPO) (3) and Cp2TiCl(4-MeO-TEMPO) (4) (TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl, 4-MeO-TEMPO = 2,2,6,6-tetramethyl-4-methoxypiperidine-N-oxyl) were conducted by nitroxyl radical exchange experiments. Eyring plots gave the activation parameters, deltaH++ = 27(+/- 1) kcal/mol, deltaS++ = 6.9(+/- 2.3) eu for 3 and deltaH++ = 28(+/- 1) kcal/mol, deltaS++ = 9.0(+/- 3.0) eu for 4, consistent with a process involving the homolysis of a weak Ti-O bond to generate the transient Cp2Ti(III)Cl and the nitroxyl radical. Thermolysis of the titanocene TEMPO complexes in the presence of epoxides leads to the Cp2Ti(III)Cl-mediated ring-opening of the epoxide followed by trapping by the nitroxyl radical. The X-ray crystal structure of the Ti-TEMPO derivative, Cp2TiCl(4-MeO-TEMPO) (4), is reported. DFT (B3LYP/6-31G*) calculations and experimental studies reveal that the strength of the Ti-O bond decreases dramatically with the number of cyclopentadienyl groups on titanium. The calculated Ti-O bond strength of the monocyclopentadienyl complex 2 is 43 kcal/mol, whereas that of the biscyclopentadienyl complex 3 is 17 kcal/mol, a difference of 26 kcal/mol. These studies reveal that the strength of these Ti-O bonds can be tuned over an interesting and experimentally accessible temperature range by appropriate ligation on titanium.     

Low-temperature rate coefficients for the reaction of ethynyl radical (C2H) with benzene

The reaction of the C2H radical with benzene is studied at low temperature using a pulsed Laval nozzle apparatus. The C2H radical is prepared by 193-nm photolysis of acetylene, and the C2H concentration is monitored using CH(A2Delta) chemiluminescence from the C2H + O2 reaction. Measurements at very low photolysis energy are performed using CF3C2H as the C2H precursor to study the influence of benzene photodissociation on the rate coefficient. Rate coefficients are obtained over a temperature range between 105 and 298 K. The average rate coefficient is found to be five times greater than the estimated value presently used in the photochemical modeling of Titan's atmosphere. The reaction exhibits a slight negative temperature dependence which can be fitted to the expression k(cm3 molecule(-1) s(-1)) = 3.28(+/-1.0) x 10(-10) (T/298)(-0.18(+/-0.18)). The results show that this reaction has no barrier and may play an important role in the formation of large molecules and aerosols at low temperature. Our results are consistent with the formation of a short lifetime intermediate that decomposes to give the final products.     

Aryl radical cyclizations: one-Pot syntheses of protoberberine and pavine alkaloids

Treatment of 2-(2'-bromo-beta-phenethyl)isocarbostyrils 7 with AIBN-Bu(3)SnH in boiling benzene gave 8-oxoberbines 3 in good yields. A similar treatment of 2-(2'-bromo-beta-phenethyl)isoquinolinium bromides 6 and their nor- and homoanalogues (10,11) induced 6-, 5-, and 7-exo radical closures in a one-pot manner to give protoberberines 2, dibenzo[b,g]indolizidine 14a and, dibenzo[a, h]-1-azabicyclo[5.4.0]undecane 15a, respectively. A one-pot radical cyclization of 1-(2'-bromobenzyl)isoquinoline methiodide 18a gave a pavine alkaloid, (+/-)-algemonine (19a).     

Free-radical approaches to stemoamide and analogues

Two approaches allowing access to the tricyclic stemona backbone are presented. Both approaches rely on a free-radical cyclization reaction as the key step. In the formal synthesis of (+/-)-stemoamide, the construction of the A ring of the natural product was achieved via a 5-exo-trig radical cyclization with atom transfer. The two diastereoisomers issuing from this cyclization showed different reactivity while forming the seven-membered ring of the final product. In the second part of this study, a 7-exo-trig free radical cyclization was realized allowing access to the (+/-)-9,10-bis-epi-stemoamide. This reaction was highly stereoselective and allowed the control of three of the four contiguous stereocenters present in the molecule.     

First experimental observation on different ionic states of the tert-butoxy [(CH3)3CO*] radical

A continuous tert-butoxy (CH3)+CO* radical beam is produced in situ by respective pyrolysis of both (CH3)3CONO at 115(+/-0.5) degrees C and (CH3)3COOC(CH3)3 at 87(+/- 0.5) degrees C. By combining the HeI photoelectron (PE) spectrum with the improved density function theory (DFT) calculations, we have concluded that the (CH3)3CO* radical has C3V symmetry and X2E ground state. The study does not only provide the ionization energies of different ionic states of the (CH3)3CO* radical for the first time, but also the first example in which there have been similar vibrational structures in different ionic states caused by removal of the electron on an orbital. It is also pointed out that (CH3)3CONO is a good source for obtaining the (CH3)3CO* radical beam, and that NO is a stable regent for the active radical. The results will promote the studies in electron spin resonance (ESR) research on the mechanisms of both the initiation of the formation of a new radical and the radical-chain polymerization in which the (CH3)3CO* radical participates.     

Formal synthesis of (+/-)-platensimycin

A formal total synthesis of (+/-)-platensimycin [(+/-)-1] is reported involving an intramolecular Stetter reaction and a radical cyclization.     

Total synthesis of (+/-)-cameroonanol

[reaction: see text]The structure and relative stereochemistry of the novel silphiperfolane-type sesquiterpene cameroonan-7alpha-ol (1) were confirmed by a total synthesis of (+/-)-1 from 3,3,5-trimethylbicyclo[3.3.0]oct-1(8)-en-2-one (6) by means of a Sakurai reaction with (Z)-crotylsilane, free radical hydrobromination, base-induced cyclization, and LiAlH4 reduction.     

Kinetics of the reactions of CH2I, CH2Br, and CHBrCl radicals with NO2 in the temperature range 220-360 K

The kinetics of the CH2I + NO2, CH2Br + NO2, and CHBrCl + NO2 reactions have been studied at temperatures between 220 and 360 K using laser photolysis/photoionization mass spectrometry. Decays of radical concentrations have been monitored in time-resolved measurements to obtain reaction rate coefficients under pseudo-first-order conditions. The bimolecular rate coefficients of all three reactions are independent of the bath gas (He or N2) and pressure within the experimental range (2-6 Torr) and are found to depend on temperature as follows: k(CH2I + NO2) = (2.18 +/- 0.07) x 10(-11) (T / 300 K)(-1.45) (+/- 0.22) cm3 molecule(-1) s(-1) (220-363 K), k(CH2Br + NO2) = (1.76 +/- 0.03) x 10(-11) (T/300 K)(-0.86) (+/- 0.09) cm3 molecule(-1) s(-1) (221-363 K), and k(CHBrCl + NO2) = (8.81 +/- 0.28) x 10(-12) (T/300 K)(-1.55) (+/- 0.34) cm3 molecule(-1) s(-1) (267-363 K), with the uncertainties given as one-standard deviations. Estimated overall uncertainties in the measured bimolecular reaction rate coefficients are about +/-25%. In the CH2I + NO2 and CH2Br + NO2 reactions, the observed product is formaldehyde. For the CHBrCl + NO2 reaction, the product observed is CHClO. In addition, I atom and iodonitromethane (CH2INO2) or iodomethyl nitrite (CH2IONO) formations have been detected for the CH2I + NO2 reaction.     

Total synthesis of (+/-)-herbertenolide by stereospecific formation of vicinal quaternary centers in a crystalline ketone

[reaction: see text] The sesquiterpene (+/-)-herbertenolide was synthesized in seven steps from commercial 2-bromo-4-methylanisole. In the key step, two adjacent stereogenic quaternary centers were controlled by a highly chemoselective and stereospecific photodecarbonylation reaction of crystalline methyl-trans-3-(2-methyl-5-methoxyphenyl)-1,3-dimethyl-2-oxocyclohexancarboxylate (3). An efficient generation of radical pairs and the stereochemical control exerted by the solid state suggest that this reaction may become a useful synthetic method.     

A short total synthesis of (+/-)-aspidospermidine

[STRUCTURE: SEE TEXT] A cascade radical cyclization starting from an amidyl radical has been used for the construction of (+/-)-aspidospermidine. This approach has also been developed for the preparation of a tricycle whose framework is contained in the stemona alkaloids.     

A short synthesis of the erythrina skeleton and of (+/-)-alpha-lycorane

[reaction: see text] A new nonchain 5-endo radical cyclization starting with xanthates was exploited in a short synthesis of (+/-)-alpha-lycorane and the erythrina ring system.     

Total synthesis of merrilactone A

Merrilactone A (1) has been shown to possess neurotrophic activity and thus is expected to hold therapeutic potential in the treatment of neurodegeneration diseases. In this paper, we report the total synthesis of (+/-)-1, employing, as key steps, a novel desymmetrization protocol of meso-diketone to construct the core cis-bicyclo[3.3.0]octyl system of 1 (3 --> 2) and a radical cyclization to install the highly congested C9-quaternary carbon (16 --> 17).     

Proton exchange kinetics from the bound waters on the oxo-centered rhodium(III) trimer [Rh3(mu3-O)(mu-O2CCH3)6(OH2)3]+: a variable pH and temperature 1H NMR study

Proton exchange from the bound to the bulk waters on the oxo-centered rhodium(III) trimer, [Rh(3)(micro(3)-O)(micro-O(2)CCH(3))(6)(OH(2))(3)](+)(abbreviated as Rh(3)(+)), was investigated over the temperature range of 219.1-313.9 K using a (1)H NMR line-broadening technique. By solving the modified Bloch equations for a two-site chemical exchange, lifetimes (tau) for proton transfer at pH = 2.7, 3.6, and 7.0 ([Rh(3)(+)]= 26 mM, T= 298 K) were determined to be 0.3 (+/-.08) ms, 2 (+/-0.3) ms, and 0.2 (+/-0.2) ms, respectively. From the temperature dependence of the rate, the activation parameters were determined to be DeltaH(++)= 16.2 (+/-0.5) kJ mol(-1) and DeltaS(++)=- 123 (+/-2) J mol(-1) K(-1), DeltaH(++)= 14.9 (+/-0.5) kJ mol(-1) and DeltaS(++)=- 141 (+/-2) J mol(-1) K(-1), and DeltaH(++)= 45 (+/-2) kJ mol(-1) and DeltaS(++)=- 22 (+/-5) J mol(-1) K(-1) for pH = 2.7, 3.6 and 7.0, respectively. All results are reported for a mixed solvent system [acetone : 250 mM NaClO(4)(aq)(3:1)], which was necessary to depress the freezing point of the solution so that the (1)H NMR signal due to bound water could be observed. The pK(a) of Rh(3)(+) was measured to be 8.9 (+/-0.2) in the mixed solvent, which is near the pK(a) for an aqueous solution (8.3 (+/-0.2)). Surprisingly, the lifetimes for protons on Rh(3)(+) are close to those observed for the Rh(OH(2))(6)(3+) ion, in spite of the considerable difference in structure, Br?nsted acidity of the bound waters and average charge on the metal ion.     

The first example of a nitrile hydratase model complex that reversibly binds nitriles

Nitrile hydratase (NHase) is an iron-containing metalloenzyme that converts nitriles to amides. The mechanism by which this biochemical reaction occurs is unknown. One mechanism that has been proposed involves nucleophilic attack of an Fe-bound nitrile by water (or hydroxide). Reported herein is a five-coordinate model compound ([Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+)) containing Fe(III) in an environment resembling that of NHase, which reversibly binds a variety of nitriles, alcohols, amines, and thiocyanate. XAS shows that five-coordinate [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) reacts with both methanol and acetonitrile to afford a six-coordinate solvent-bound complex. Competitive binding studies demonstrate that MeCN preferentially binds over ROH, suggesting that nitriles would be capable of displacing the H(2)O coordinated to the iron site of NHase. Thermodynamic parameters were determined for acetonitrile (DeltaH = -6.2(+/-0.2) kcal/mol, DeltaS = -29.4(+/-0.8) eu), benzonitrile (-4.2(+/-0.6) kcal/mol, DeltaS = -18(+/-3) eu), and pyridine (DeltaH = -8(+/-1) kcal/mol, DeltaS = -41(+/-6) eu) binding to [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) using variable-temperature electronic absorption spectroscopy. Ligand exchange kinetics were examined for acetonitrile, iso-propylnitrile, benzonitrile, and 4-tert-butylpyridine using (13)C NMR line-broadening analysis, at a variety of temperatures. Activation parameters for ligand exchange were determined to be DeltaH(+ +) = 7.1(+/-0.8) kcal/mol, DeltaS(+ +) = -10(+/-1) eu (acetonitrile), DeltaH(+ +) = 5.4(+/-0.6) kcal/mol, DeltaS(+ +) = -17(+/-2) eu (iso-propionitrile), DeltaH(+ +) = 4.9(+/-0.8) kcal/mol, DeltaS(+ +) = -20(+/-3) eu (benzonitrile), and DeltaH(+ +) = 4.7(+/-1.4) kcal/mol DeltaS(+ +) = -18(+/-2) eu (4-tert-butylpyridine). The thermodynamic parameters for pyridine binding to a related complex, [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) (DeltaH = -5.9(+/-0.8) kcal/mol, DeltaS = -24(+/-3) eu), are also reported, as well as kinetic parameters for 4-tert-butylpyridine exchange (DeltaH(+ +) = 3.1(+/-0.8) kcal/mol, DeltaS(+ +) = -25(+/-3) eu). These data show for the first time that, when it is contained in a ligand environment similar to that of NHase, Fe(III) is capable of forming a stable complex with nitriles. Also, the rates of ligand exchange demonstrate that low-spin Fe(III) in this ligand environment is more labile than expected. Furthermore, comparison of [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) and [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) demonstrates how minor distortions induced by ligand constraints can dramatically alter the reactivity of a metal complex.     

Electron capture dissociation mass spectrometry of peptide cations containing a lysine homologue: a mobile proton model for explaining the observation of b-type product ions

Eleven doubly protonated peptides with a residue homologous to lysine were investigated by electron capture dissociation mass spectrometry (ECD-MS). Lysine homologues provide the unique opportunity to examine the ECD fragmentation behavior by allowing us to vary the length of the lysine side chain, with minimal structural change. The lysine homologue has a primary amine side chain with a length that successively decreases by one methylene (CH(2)) unit from the --CH(2)CH(2)CH(2)CH(2)NH(2) of lysine and the accompanying decrease of its proton affinities: lysine (K), 1006.5(+/-7.2) kJ/mol; ornithine (K(*)), 1001.1(+/-6.6) kJ/mol; 2,4-diaminobutanoic acid (K(**)), 975.8(+/-7.4) kJ/mol; 2,3-diaminopropanoic acid (K(***)), 950.2(+/-7.2) kJ/mol. In general, the lysine-homologous peptides exhibited overall ECD fragmentation patterns similar to that of the lysine-containing peptides in terms of the locations, abundances, and ion types of products, such as yielding c(+) and z(+.) ions as the dominant product ions. However, a close inspection of product ion mass spectra showed that ECD-MS for the alanine-rich peptides with an ornithinyl or 2,4-diaminobutanoyl residue gave rise to b ions, while the lysinyl-residue-containing peptides did not, in most cases, produce any b ions. The peptide selectivity in the generation of b(+) ions could be understood from within the framework of the mobile proton model in ECD-MS, previously proposed by Cooper (Ref. 29). The exact mass analysis of the resultant b ions reveals that these b ions are not radical species but rather the cationic species with R-CO(+) structure (or protonated oxozalone ion), that is, b(+) ions. The absence of [M+2H](+.) species in the ECD mass spectra and the selective b(+)-ion formation are evidence that the peptides underwent H-atom loss upon electron capture, and then the resulting reduced species dissociated following typical MS/MS fragmentation pathways. This explanation was further supported by extensive b(+) ions generated in the ECD of alanine-based peptides with extended conformations.     

Theory of multichannel thermal unimolecular reactions. 2. Application to the thermal dissociation of formaldehyde

The thermal dissociation of formaldehyde proceeds on three channels, the molecular-elimination channel H2CO --> H2 + CO (1), the radical-forming bond-fission channel H2CO --> H + HCO (2), and the bond-fission-initiated, intramolecular-hydrogen-abstraction channel H2CO --> H...HCO --> H2 + CO (3) which also forms molecular products. The kinetics of this system in the low-pressure range of the unimolecular reaction is shown to be governed by a subtle superposition of collisional channel coupling to be treated by solving a master equation, of rotational channel switching accessible through ab initio calculations of the potential as well as spectroscopic and photophysical determinations of the threshold energies and channel branching above the threshold energy for radical formation which can be characterized through formaldehyde photolysis quantum yields as well as classical trajectory calculations. On the basis of the available information, the rate coefficients for the formation of molecular and radical fragments are analyzed and extrapolated over wide ranges of conditions. The modeled rate coefficients in the low-pressure range of the reaction (neglecting tunneling) over the range 1400-3200 K in the bath-gas Ar in this way are represented by k0,Mol/[Ar] approximately 9.4 x 10(-9) exp(-33,140 K/T) cm3 molecule(-1) s(-1) and k0,Rad/[Ar] approximately 6.2 x 10(-9) exp(-36,980 K/T) cm3 molecule(-1) s(-1). The corresponding values for the bath-gas Kr, on which the analysis relies in particular, are k0,Mol/[Kr] approximately 7.7 x 10(-9) exp(-33,110 K/T) and k0,Rad/[Kr] approximately 4.1 x 10(-9) exp(-36 910 K/T) cm3 molecule(-1) s(-1). While the threshold energy E0,2 for channels 2 and 3 is taken from spectroscopic measurements, the threshold energy E0,1 for channel 1 is fitted on the basis of experimental ratios k0,Rad/k0,Mol in combination with photolysis quantum yields. The derived value of E0,1(1) = 81.2 (+/-0.9) kcal mol(-1) is in good agreement with results from recent ab initio calculations, 81.9 (+/-0.3) kcal mol(-1), but is higher than earlier results derived from photophysical experiments, 79.2 (+/-0.8) kcal mol(-1). Rate coefficients for the high-pressure limit of the reaction are also modeled. The results of the present work markedly depend on the branching ratio between channels 2 and 3. Expressions of this branching ratio from classical trajectory calculations and from photolysis quantum yield measurements were tested. At the same time, a modeling of the photolysis quantum yields was performed. The formaldehyde system so far presents the best characterized multichannel dissociation reaction. It may serve as a prototype for other multichannel dissociation reactions.     

Self-sorting molecular clips

We report the synthesis and characterization of 12 C-shaped methylene-bridged glycoluril dimers (1-12) bearing H-bonding groups on their aromatic rings. Compounds 1, 2, (+/-)-4a, (+/-)-5, (+/-)-7, and 8 form tightly associated homodimers in CDCl3, due to the combined driving force of pi-pi and H-bonding interactions. Compounds 2, (+/-)-5, and 8, having disparate spatial distribution of their H-bonding groups, display the ability to efficiently distinguish between self and nonself even within three-component mixtures in CDCl3. When the spatial distributions of the H-bonding groups of the molecular clips are similar (e.g., 1 and 2), a mixture of homodimers and heterodimers is formed. The effect of various structural modifications (e.g., chirality, side chain steric bulk, number and pattern of H-bonds) on the strength of self-assembly and the fidelity of self-sorting are presented. On the basis of these results we prepared self-sorting systems comprising three (e.g., 1, (+/-)-5, and (+/-)-7) and even four ( 2, (+/-)-5, 9, and 10) components. The potential of molecular clips 1-12 as robust, functionalizable, self-sorting modules to control the noncovalent interaction network in systems chemistry studies is described.     

Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: total synthesis of (+/-)-20-deoxycamptothecin and (+)-camptothecin

Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition of alpha-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts, respectively. Addition of the enolate derived from isopropyl alpha-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which (+/-)-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective reduction. A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative (33) provides access to natural (+)-camptothecin (37).